tbuckley/cabot-search huggingface dataset:
Chronic myeloid leukemia without major molecular response after 2 years of treatment with tyrosine kinase inhibitor
Authors: Aram Bidikian, Elias Jabbour, Ghayas C. Issa, Nicholas J. Short, Koji Sasaki, Hagop Kantarjian
Journal: American Journal of Hematology (2023)

Achieving major molecular response (MMR) with BCR::ABL1 tyrosine kinase inhibitors (TKIs) is associated with lower chances of progression to advanced phase disease and higher chances of treatment-free remission (TFR) in patients with chronic myeloid leukemia (CML). Failure to achieve this molecular milestone after 1 year has been highlighted as "suboptimal" or "warning" sign of treatment failure in CML guidelines and recommendations and implied to predict a poor long-term outcome. In this analysis, we report the long-term outcome of 131 patients who did not achieve MMR within the first 2 years of TKI therapy. Patients who achieved a major cytogenetic response (MCyR; roughly equivalent to BCR::ABL1 transcript levels on the International Scale [IS] <10%) had good long-term overall survival (OS) (10-year OS of 88%) and CML-related overall survival (CML-OS) (10-year CML-OS of 95%). The achievement of MCyR within the first 2 years of treatment predicted a better OS (HR = 0.43, p = .03). The value of MMR was even less pronounced among patients aged 60 years or older at diagnosis, in whom mortality was primarily due to comorbidities unrelated to CML (10-year OS of 55% vs. 10-year CML-OS of 100%). In conclusion, achievement of MCyR within 2 years is a reasonable milestone in CML, and these patients can still have good outcomes even when MMR is not achieved.
Sequence analyses of relapsed or refractory diffuse large B‐cell lymphomas unravel three genetic subgroups of patients and the <scp><i>GNA13</i></scp> mutant as poor prognostic biomarker, results of <scp>LNH‐EP1</scp> study
Authors: Jean‐Marie Michot, Cyril Quivoron, Clémentine Sarkozy, Alina Danu, Julien Lazarovici, Khalil Saleh, Yolla El‐Dakdouki, Vincent Goldschmidt, Camille Bigenwald, Matteo Dragani, Rastislav Bahleda, Capucine Baldini, Julia Arfi‐Rouche, Patricia Martin‐Romano, Lambros Tselikas, Anas Gazzah, Antoine Hollebecque, Ludovic Lacroix, David Ghez, Veronique Vergé, Christophe Marzac, Sophie Cotteret, Wassila Rahali, Jean‐Charles Soria, Christophe Massard, Olivier A. Bernard, Peggy Dartigues, Valérie Camara‐Clayette, Vincent Ribrag
Journal: American Journal of Hematology (2023)

Advances in molecular profiling of newly diagnosed diffuse large B-cell lymphoma (DLBCL) have recently refine genetic subgroups. Genetic subgroups remain undetermined at the time of relapse or refractory (RR) disease. This study aims to decipher genetic subgroups and search for prognostic molecular biomarkers in patients with RR-DLBCL. From 2015 to 2021, targeted next-generation sequencing analyses of germline-matched tumor samples and fresh tissue from RR-DLBCL patients were performed. Unsupervised clustering of somatic mutations was performed and correlations with patient outcome were sought. A number of 120 patients with RR-DLBCL were included in LNH-EP1 study and a molecular tumor landscape was successfully analyzed in 87% of patients (104/120 tumor samples). The median age was 67.5 years (range 27.4-87.4), median number of previous treatments was 2 (range 1-9). The most frequently mutated genes were TP53 (n = 53 mutations; 42% of samples), CREBBP (n = 39; 32%), BCL2 (n = 86; 31%), KMT2D (n = 39; 28%) and PIM1 (n = 54; 22%). Unsupervised clustering separated three genetic subgroups entitled BST (enriched in BCL2, SOCS1, and TNFRSF14 mutations); TKS (enriched in TP53, KMT2D, and STAT6 mutations); and PCM (enriched in PIM1, CD79B, and MYD88 mutations). Median overall survival (OS) was 11.0 (95% confidence interval [CI]: 8.1-12.6) months. OS was not significantly different between the three genetic subgroups. GNA13 mutant was significantly associated with an increased risk of death (hazard ratio: 6.6 [95% CI: 2.1-20.6]; p = .0011) and shorter OS (p = .0340). At the time of relapse or refractory disease, three genetic subgroups of DLBCL patients were delineated, which could help advance precision molecular medicine programs.
Examining the prevalence of trans phantoms among transgender, nonbinary and gender diverse individuals: An exploratory study
Authors: S. J. Langer, Taymy Josefa Caso, Louisa Gleichman
Journal: International Journal of Transgender Health (2023)

Background Trans phantoms are bodily sensations of gendered body parts that a person was not born with (i.e., a phantom penis experienced by a trans man, or a phantom vagina experienced by a trans woman). This is distinct from the experience of many transgender and gender diverse (TGD) people, who experience awareness of their bodies as missing a gendered body part, or configuration, which is a major characteristic of gender dysphoria.Aims Our purpose was to gain greater understanding of the prevalence and quality of trans phantoms.Methods Data was gathered through a brief, online survey on trans embodiment. Respondents who had both completed the survey, and were deemed appropriate for inclusion in the study, based on their survey responses, comprised our sample of 1,446 adults.Results Results indicated that trans phantoms are a typical embodied experience of TGD people. Almost 50% of study participants reported experiencing a trans phantom, most of whom also reported feeling erotic sensation in their phantom.Conclusions Though the phenomenon of trans phantoms is not universal, it is clearly one that warrants further study.
Teaching an old dog new tricks: re-engineering IL-2 for immuno-oncology applications
Authors: Mario Sznol, Naiyer Rizvi
Journal: Journal for ImmunoTherapy of Cancer (2023)

Various approaches are being explored to address the unmet medical need among patients with advanced cancer who do not respond to immune checkpoint inhibitors. Interleukin-2 has become a prominent focus of preclinical and clinical investigation, because of its known clinical activity, the important role of this cytokine in immune biology, and the ability to engineer variant proteins with potentially improved antitumor immunomodulatory activity and reduced toxicity. Bempegaldesleukin, the first of the modified IL-2 agents to reach phase 3 evaluation in combination with an anti-PD-1, did not improve outcome for patients with metastatic melanoma and renal carcinoma. The disappointing data raise important questions about the potential efficacy of other interleukin-2 variants, however, several of the other variants appear to be sufficiently differentiated in anticipated pharmacokinetic properties and immune modulatory effects to warrant continued clinical development.
USP48 Stabilizes Gasdermin E to Promote Pyroptosis in Cancer
Authors: Yidan Ren, Maoxiao Feng, Xiaodong Hao, Xiaoyan Liu, Juan Li, Peilong Li, Jie Gao, Qiuchen Qi, Lutao Du, Chuanxin Wang, Qin Wang, Yunshan Wang
Journal: Cancer Research (2023)

Pyroptosis is a type of programmed cell death characterized by the activation of inflammatory caspases and the cleavage of gasdermin proteins. Pyroptosis can suppress tumor development and induce antitumor immunity, and activating pyroptosis is a potential treatment strategy for cancer. To uncover approaches to harness the anticancer effects of pyroptosis, we aimed to identify regulators of pyroptosis in cancer. A CRISPR-Cas9 screen identified that loss of USP48, a deubiquitinating enzyme, significantly inhibited cell pyroptosis. USP48 promoted pyroptosis by stabilizing gasdermin E (GSDME). USP48 bound GSDME and removed K48-linked ubiquitination at positions K120 and K189. Clinical tissue testing confirmed that the expression of USP48 positively correlated with GSDME and pyroptosis-related factors. Single-cell sequencing showed that the functions of T cells and tumor-associated macrophages in the tumor microenvironment were inhibited after USP48 knockout. Finally, overexpression of USP48 enhanced the therapeutic efficacy of programmed cell death protein 1 inhibitors in tumors in mouse models. Together, these findings define a pyroptosis regulation pathway and indicate that pharmacologic activation of USP48 may provide an effective strategy to sensitize cancer cells to pyroptosis and improve response to immunotherapy.USP48 promotes pyroptosis by deubiquitinating GSDME and enhances antitumor immunity, indicating that increasing USP48 activity may be a future therapeutic strategy for treating cancer.
Spheres of Morality: The Ethical Codes of the Medical Profession
Authors: Samuel Doernberg, Robert Truog
Journal: The American Journal of Bioethics (2023)

The medical profession contains five "spheres of morality": clinical care, clinical research, scientific knowledge, population health, and the market. These distinct sets of normative commitments require physicians to act in different ways depending on the ends of the activity in question. For example, a physician-scientist emphasizes patients' well-being in clinic, prioritizes the scientific method in lab, and seeks to maximize shareholder returns as a board member of a pharmaceutical firm. Physicians increasingly occupy multiple roles in healthcare and move between them frequently, creating the possibility of conflict between the ethical obligations of their various roles. This paper examines the entire moral landscape of medicine through the lens of role morality. It develops a novel framework that helps physicians recognize how their moral commitments depend on the nature and context of the situation, clarifies ethical conflicts that physicians face, and concludes with ideas for resolving these conflicts.
Hyperbaric oxygen facilitates teniposide-induced cGAS-STING activation to enhance the antitumor efficacy of PD-1 antibody in HCC
Authors: Kui-Sheng Yang, Chuan-Qi Xu, Jian Lv
Journal: Journal for ImmunoTherapy of Cancer (2023)

Recently, we followed the report by Yang et al that hyperbaric oxygen facilitates teniposide-induced The cyclic GMP–AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway(cGAS-STING) activation to enhance the antitumor efficacy of an anti-PD-1 antibody in Hepatocellular carcinoma (
Long-Term Exposure to Transportation Noise and Ischemic Heart Disease: A Pooled Analysis of Nine Scandinavian Cohorts
Authors: Andrei Pyko, Nina Roswall, Mikael Ögren, Anna Oudin, Annika Rosengren, Charlotta Eriksson, David Segersson, Debora Rizzuto, Eva M. Andersson, Gunn Marit Aasvang, Gunnar Engström, Hrafnhildur Gudjonsdottir, Jeanette T. Jørgensen, Jenny Selander, Jesper H. Christensen, Jørgen Brandt, Karin Leander, Kim Overvad, Kristina Eneroth, Kristoffer Mattisson, Lars Barregard, Leo Stockfelt, Maria Albin, Mette K. Simonsen, Pekka Tiittanen, Peter Molnar, Petter Ljungman, Steen Solvang Jensen, Susanna Gustafsson, Timo Lanki, Youn-Hee Lim, Zorana J. Andersen, Mette Sørensen, Göran Pershagen
Journal: Environmental Health Perspectives (2023)

Background: Transportation noise may induce cardiovascular disease, but the public health implications are unclear. Objectives: The study aimed to assess exposure–response relationships for different transportation noise sources and ischemic heart disease (IHD), including subtypes. Methods: Pooled analyses were performed of nine cohorts from Denmark and Sweden, together including 132,801 subjects. Time-weighted long-term exposure to road, railway, and aircraft noise, as well as air pollution, was estimated based on residential histories. Hazard ratios (HRs) were calculated using Cox proportional hazards models following adjustment for lifestyle and socioeconomic risk factors. Results: A total of 22,459 incident cases of IHD were identified during follow-up from national patient and mortality registers, including 7,682 cases of myocardial infarction. The adjusted HR for IHD was 1.03 [95% confidence interval (CI) 1.00, 1.05] per 10 dB Lden for both road and railway noise exposure during 5 y prior to the event. Higher risks were indicated for IHD excluding angina pectoris cases, with HRs of 1.06 (95% CI: 1.03, 1.08) and 1.05 (95% CI: 1.01, 1.08) per 10 dB Lden for road and railway noise, respectively. Corresponding HRs for myocardial infarction were 1.02 (95% CI: 0.99, 1.05) and 1.04 (95% CI: 0.99, 1.08). Increased risks were observed for aircraft noise but without clear exposure–response relations. A threshold at around 55 dB Lden was suggested in the exposure–response relation for road traffic noise and IHD. Discussion: Exposure to road, railway, and aircraft noise in the prior 5 y was associated with an increased risk of IHD, particularly after exclusion of angina pectoris cases, which are less well identified in the registries. https://doi.org/10.1289/EHP10745
Integrative Single-Cell Analysis Reveals Transcriptional and Epigenetic Regulatory Features of Clear Cell Renal Cell Carcinoma
Authors: Zhenyuan Yu, Yufang Lv, Cheng Su, Wenhao Lu, RuiRui Zhang, Jiaping Li, Bingqian Guo, Haibiao Yan, Deyun Liu, Zhanbin Yang, Hua Mi, Linjian Mo, Yi Guo, Wenyu Feng, Haotian Xu, Wenyi Peng, Jiwen Cheng, Aruo Nan, Zengnan Mo
Journal: Cancer Research (2023)

Abstract Clear cell renal cell carcinoma (ccRCC) frequently features a high level of tumor heterogeneity. Elucidating the chromatin landscape of ccRCC at the single-cell level could provide a deeper understanding of the functional states and regulatory dynamics underlying the disease. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell assay for transposase-accessible chromatin using sequencing (scATAC-seq) on 19 ccRCC samples, and whole-exome sequencing was used to understand the heterogeneity between individuals. Single-cell transcriptome and chromatin accessibility maps of ccRCC were constructed to reveal the regulatory characteristics of different tumor cell subtypes in ccRCC. Two long noncoding RNAs (RP11-661C8.2 and CTB-164N12.1) were identified that promoted the invasion and migration of ccRCC, which was validated with in vitro experiments. Taken together, this study comprehensively characterized the gene expression and DNA regulation landscape of ccRCC, which could provide new insights into the biology and treatment of ccRCC. Significance: A comprehensive analysis of gene expression and DNA regulation in ccRCC using scATAC-seq and scRNA-seq reveals the DNA regulatory programs of ccRCC at the single-cell level.
The BMJ Appeal 2022-23: Cholera on the rise and how IFRC is working to fight it
Authors: Jane Feinmann
Journal: BMJ (2023)

Cholera affects the world's poorest people in communities lacking adequate sanitation or safe drinking water. <b>Jane Feinmann</b> follows the work of the International Federation of Red Cross and Red Crescent Societies in fighting this easily treated, yet rising, worldwide threat
Sixty seconds on . . . aeroplane waste
Authors: Elisabeth Mahase
Journal: BMJ (2023)

Blue sky thinking?The US Centers for Disease Control and Prevention (CDC) is reportedly considering sampling aeroplane wastewater in an attempt to track new SARS-CoV-2 variants from China. 1 The idea is being floated in response to the resurgence of covid-19 in China, with modellers predicting cases could hit 3.7m a day by 13 January with deaths potentially rising to 25 000 a day around 10 days later. 2 Could it be piloted?While it's still being considered by the CDC, it's not such a fanciful idea.Wastewater sampling-also referred to as sewage monitoring-has been used as part of public health plans for decades, including during the US polio outbreaks in 1939.In the UK in recent years it has been used during the covid-19 pandemic to monitor SARS-CoV-2 and also enabled officials to spot poliovirus in London. 3 Sounds plane and simple . . .Wastewater sampling works because people infected with SARS-CoV-2 can shed the virus in their faeces, even when asymptomatic.In December 2021, researchers from France tested the wastewater of two planes arriving in Marseille from Addis Ababa, Ethiopia, and found that while mandatory predeparture covid-19 testing was in place, traces of the virus were still detected and a significant number of passengers were found to be infected. 4 A waste of time?Since covid-19 is now endemic across the UK and US, with both countries removing the control measures that had kept infection levels at a lower level, it is reasonable to ask whether testing aeroplane wastewater could really make a difference.The answer seems to be no, and yes.
Associations of cardiorespiratory fitness and body mass index with incident restrictive spirometry pattern
Authors: Joey M Saavedra, Angelique G Brellenthin, Bong Kil Song, Duck-chul Lee, Xuemei Sui, Steven N Blair
Journal: British Journal of Sports Medicine (2023)

Restrictive spirometry pattern (RSP) suggests an impairment of lung function associated with a significantly increased risk of premature mortality. We evaluated the independent and joint associations of cardiorespiratory fitness (CRF) and body mass index with incident RSP.Data from the Aerobics Centre Longitudinal Study included 12 360 participants (18-82 years). CRF was assessed by maximal treadmill test and categorised into five groups. Body mass index was categorised into normal weight (<25.0 kg/m2), overweight (25.0-29.9 kg/m2) or obesity (≥30.0 kg/m2). RSP was defined as the simultaneous occurrence of forced expiratory volume in 1 s/force vital capacity ≥lower limit of normal and forced vital capacity <lower limit of normal.There were 900 (7.3%) cases of RSP (mean follow-up: 6.9 years). Compared with category 1 ('least fit'), HRs (95% CIs) of RSP were 0.78 (0.63 to 0.96), 0.68 (0.54 to 0.86), 0.70 (0.55 to 0.88) and 0.59 (0.45 to 0.77) in categories 2, 3, 4 and 5 (most fit), respectively, after adjusting for confounders including body mass index. Compared with normal weight, HRs (95% CIs) of RSP were 1.06 (0.91 to 1.23) and 1.30 (1.03 to 1.64) in overweight and obese, respectively. However, the association between obesity and RSP was attenuated when additionally adjusting for CRF (HR 1.08, 95% CI 0.84 to 1.39). Compared with the 'unfit and overweight/obese' group, HRs (95% CIs) for RSP were 1.35 (0.98 to 1.85), 0.77 (0.63 to 0.96) and 0.70 (0.56 to 0.87) in the 'unfit and normal weight,' 'fit and overweight/obese' and 'fit and normal weight' groups, respectively.Low CRF was associated with a greater incidence of RSP, irrespective of body mass index. Future studies are needed to explore potential underlying mechanisms of this association and to prospectively evaluate if improving CRF reduces the risk of developing RSP.
Aortitis PET Imaging in VEXAS Syndrome
Authors: Julia Grambow-Velilla, Thorsten Braun, Gabriel Pop, Astrid Louzoun, Michael Soussan
Journal: Clinical Nuclear Medicine (2022)

Abstract VEXAS (vacuoles, E1 enzyme, X-LINKED, autoinflammatory, somatic) syndrome is a complex inflammatory disease associated with somatic mutations of the ubiquitin-like modifier activating enzyme 1 ( UBA1 ) gene. A 75-year-old man with a medical history of thrombophlebitis, leukocytoclastic vasculitis, chronic inflammatory arthralgia, elevated inflammatory markers, and anemia was diagnosed with VEXAS syndrome. 18 F-FDG PET/CT showed thoracic aortitis, a rare involvement during VEXAS syndrome. Corticosteroid therapy monitored with 18 F-FDG PET/CT led to a complete metabolic response.
Increased FAPI Activity in Pulmonary Tuberculosis
Authors: Wei Liu, Weidong Gong, Xiao Yang, Tingting Xu, Yue Chen
Journal: Clinical Nuclear Medicine (2022)

Abstract A 50-year-old man presented with cough and hemoptysis for 1 month. Chest CT showed an irregular mass in the right lung, with enlarged lymph nodes in the mediastinum and right hilum. These findings were suggestive of lung cancer with lymph node metastases. The patient was subsequently enrolled in a 68 Ga-DOTA-FAPI-04 PET/CT clinical trial. 68 Ga-DOTA-FAPI-04 PET/CT revealed a mass in the upper lobe of right lung, with intense tracer uptake. Meanwhile, PET/CT showed enlarged lymph nodes in the mediastinum and right hilum, with mild FAPI uptake. However, pathological examination confirmed the mass was tuberculous granuloma.
Striatal Dopaminergic Loss and Dysphagia in Parkinson Disease
Authors: Ji Hwan Kim, Jonghu Jeon, Young Lee, Seung Min Kim, Miju Cheon, Jun Yup Kim
Journal: Clinical Nuclear Medicine (2022)

To better understand the development of dysphagia in patients with Parkinson disease (PD) and to identify possible neuromodulatory target regions of dysphagia, we studied the striatal dopamine transporter (DAT) availability distribution by subtype of dysphagia.In this retrospective cross-sectional study, patients with PD who underwent videofluoroscopic swallowing study and N-(3-[18F]fluoropropyl)-2β-carbon ethoxy-3β-(4-iodophenyl) nortropane (18F-FP-CIT) PET at intervals of less than 1 month were analyzed. The 14 binarized subitem scores of the Videofluoroscopic Dysphagia Scale were analyzed using a voxel-wise Firth's penalized binary logistic regression model, adjusting for age and disease duration at videofluoroscopic swallowing study.Sixty-five patients with PD were finally included. Striatal mapping showed association of decreased DAT availability with 5 subitems with 1 or more clusters surviving the statistical threshold: 1 oral phase and 4 pharyngeal phase subitems. The overlap maps created by superimposing clusters for all 5 statistically significant subitems revealed associations of dysphagia in PD with decreased DAT availability in the bilateral ventral striatum. Of these, 4 subitems belonging to the pharyngeal phase-specific dysphagia were additionally found to be related to dopaminergic degeneration of the bilateral anterior-to-posterior caudate and ventral striatum.These findings suggest that subitem/phase-specific striatal subregional dopaminergic depletion may explain the dysphagia of PD. This dopaminergic degeneration of striatal subregions specific to the phases of dysphagia may serve as a potential target for neuromodulatory brain stimulation through stimulation of cortices functionally connected.
Unintentional Intra-arterial Injection of 177Lu-PSMA-1 in a Patient With a Peritoneal Carcinosis Secondary to a Metastatic Prostate Cancer
Authors: David Kryza, Aurélie Moreau, Jean Noël Badel, Thomas Mognetti, Anne Laure Giraudet
Journal: Clinical Nuclear Medicine (2022)

We report the case of an 81-year-old man presenting with peritoneal carcinosis secondary to a metastatic castrate-resistant prostate cancer addressed for 177Lu-PSMA-1 therapy. During the second cycle, a diffuse uptake in his left forearm was observed on the 1-hour postinjection scintigraphy, typical for an accidental intra-arterial injection. Less than 24 hours postinjection, a full removal of the intra-arterial injection was observed in the man, without any pain or symptoms. Moreover, the man demonstrated an 85% PSA reduction and a CT OR following the RECIST 1.1 criteria after 3 cycles.
Progressive Transformation of Germinal Centers Simulating Malignant Axillary Lymphadenopathy in a Breast Cancer Patient on FDG PET/CT
Authors: Nir Hod, Karen Nalbandyan, Tzvika Porges, Sophie Lantsberg
Journal: Clinical Nuclear Medicine (2022)

A 64-year-old woman with breast cancer underwent FDG PET/CT for follow-up. The study revealed highly increased FDG uptake in newly diagnosed enlarged axillary lymph nodes, which were worrisome for malignancy. Histopathology revealed a rarely diagnosed benign disease of progressive transformation of germinal centers mimicking malignant lymphadenopathy. As imaging findings of this entity, which usually involves the axillary and cervical areas, have been reported in very few studies, nuclear medicine physicians should be familiar with this potential “false-positive” FDG uptake representing an interpretative pitfall, especially during evaluation of breast cancer patients.